This invention relates to medicine. In particular, it relates to a novel transdermal drug delivery system and a process for preparing the same whereby a therapeutically effective dose of Huperzine A (xe2x80x9cHup Axe2x80x9d) can be transdermally administered to patients for the treatment of Alzheimer""s Disease (xe2x80x9cADxe2x80x9d).
AD is thought to be the disease of 21 century. It accounts for about 75% of senile dementia. This central nervous system disorder is marked by a variety of symptoms such as degeneration of neurons, development of amyloid plaques, neurofibrillary tangles, declination of acetylcholine and atrophy of cerebral cortex. Patients with AD suffer loss of short-term memory initially and followed by decline in cognitive function and finally loss of the ability to care for themselves.
AD affects about 10% of the population who are beyond age 65. It attacks 19% of individuals 75 to 85 years old, and 45% over age 85. AD is the fourth leading cause of death in adults, behind heart disease, cancer, and stroke. The cost of caring for patients, including diagnosis, nursing, at-home care, and lost wages combined, is estimated to be between $80 billion and $90 billion per year.
Although there are progresses in unfolding pathophysiologic mechanisms of the disease, the cause of AD is still poorly understood. There are several suspected causes such as genetic predisposition (PS-1, PS-2, APP, apoE, CO1, CO2 gene mutations), neurotransmitter defects (Acetylcholine deficiency), inflammation, metabolic decline, free radical stress, or excitatory amino acid toxicity. None of these causes alone is conclusive.
Several compounds are currently under clinical studies for AD according to the current understanding of its pathogenesis. Among these drugs notably are acetylcholine esterase (AchE) inhibitors. Recently, two AchE inhibitors, Tacrine and Donepezil, have received regulatory approval for AD treatment. While Tacrine provides a moderate beneficial effect on deterioration of cognition, it suffers some adverse effects as it causes increases in serum hepatic enzymes. Several other AchE inhibitors with higher potency and better specificity are under clinical investigations. One of these AchE inhibitors is Hup A.
Hup A is an alkaloid isolated from Lycopodium serratum, a Chinese traditional medicinal herb. Hup A appears to be more specific and potent in inhibiting AchE compared to Tacrine and Donepezil as demonstrated in both in vitro and in animal model. The three dimensional crystal structure of the AchE/Hup complex shows a strong hydrophobic interaction between Hup A and the active-site gorge of AchE. Further studies have shown that Hup A is able to permeate through the blood-brain barrier to produce a dose-dependent increase of Ach, norepinephrine, and dopamine in rat cortex by systemic or local administration of Hup A. It appears that Hup A demonstrates promising protective effects to neuron from neurotoxins. Evidences obtained from studies employed rat embryo hippocampus and cerebellum cultured cells have shown that Hup A decreases the death of neuronal cell caused by toxic levels of glutamate. The pharmaco-kinetics evaluation of a single oral dose of 0.99 mg of Hup A to six volunteers showed that Hup A was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate. In a small double blind clinical study conducted in China, Hup A administered orally at 0.2 mg (4 tablets, b.i.d) for 8 weeks had demonstrated significant improvement in memory, cognition and behavior in 58% patients without causing any severe side effects to the same.
Administration of drugs for AD patients has to be made convenient for self-medication of the patients as well as for medication rendered by care-givers. Especially in those elderly suffering from memory disorders and dementia, repeated administration of drugs may be difficult as they tend to miss scheduled self-medication or otherwise may require the care-givers to expend extra time ensuring that AD patients are adhered to their medication schedules.
There is therefore an apparent need for drug delivery formulations and a process of making the same which would allow transdermal delivery of Hup A to AD patients at a constant rate for over a period of time after a single Hup A administration such that the patients are assured to receive adequate medication without the need of constant monitoring and supervision.
It is therefore an object of the invention to provide for such novel transdermal drug delivery formulations and process for Hup A through a long-term controlled release skin patch of Hup A for treatment of AD patients.
It is another object of the invention to provide for a method for transdermal Hup A administration through a long-term controlled release skin patch of Hup A to provide therapeutical benefits for AD patients.
It is one more object of the invention to provide a long-term controlled release skin patch of Hup A that will provide therapeutical benefits to AD patients for at least seven (7) days.
These objects are realized by the invention by providing a controlled release skin patch designed for once-a-day or once-a-week application to provide a consistent and systematic method for delivering Hup A to AD patients without constant monitoring and supervision for several days after a single administration.
This invention relates to a novel transdermal delivery device for a pharmaceutical composition comprising Hup A which has been proven to reduce and temper the effects of Alzheimer""s Disease.
One aspect of the invention is to provide for a transdermal drug delivery device suitable for transdermal administration of Hup A to provide therapeutical benefits to patients with Alzheimer disease. The transdermal drug delivery device comprises (i) a concentration of Hup A in an amount sufficient to enable said Hup A to exhibit anti-Alzheimer activity through said transdermal administration; (ii) at least an aprotic solvent in a concentration sufficient to dissolve said Hup A to from a Hup A reservoir; (iii) a gelling agent in an amount sufficient to gelled said Hup A reservoir; and (iv) at least a polymeric membrane added to encapsulate said gelled Hup A reservoir to form a controlled-release formulation. The Hup A reservoir is adjusted to a pH range in which said Hup A is predominantly in a neutral form to achieve maximum transdermal delivery of said Hup A to provide the therapeutical benefits to the patients. The transdermal drug delivery device according to the invention may be in a form of skin patch with the aid of a drug-impermeable metallic-plastic laminate to said polymeric membrane. Preferably, the pH range of the Hup A reservoir is between 7 to 9.
Another aspect of the invention is to provide for an adhesive-type transdermal drug delivery device suitable for transdermal administration of Hup A to provide therapeutical benefits to patients with Alzheimer disease. Briefly, the adhesive-type transdermal drug delivery device comprises (i) a concentration of Hup A in an amount sufficient to enable said Hup A to exhibit anti-Alzheimer activity through said transdermal administration; (ii) at least a pressure-sensitive adhesive polymer in a concentration sufficient to dissolve said Hup A to from a Hup A adhesive solution in presence of an organic solvent; and (iii) a sheet of drug-impermeable backing laminate added to coat said Hup A adhesive solution to form a pressure-sensitive adhesive formulation. Preferably, the Hup A adhesive solution has a pH value in the range of 7 to 9.
One more aspect of the invention is to provide for a method for preparing the aforementioned transdermal drug delivery device which comprises weighing a concentration of Hup A in an amount sufficient to enable said Hup A to exhibit anti-Alzheimer activity through transdermal administration; dissolving said Hup A in at least an aprotic solvent in a pH range enabling said Hup A existing predominantly in a neutral form to form a Hup A reservoir; adding a gelling agent to gell said Hup A reservoir; and adding at least a polymeric membrane to encapsulate said gelled Hup A reservoir to form a controlled-release formulation.
One further aspect of the invention is to provide for a method for preparing the aforementioned adhesive-type transdermal drug delivery device which comprises weighing a concentration of Hup A in an amount sufficient to enable said Hup A to exhibit anti-Alzheimer activity through transdermal administration; dissolving said Hup A in at least a pressure-sensitive adhesive polymer in presence of a suitable solvent to from a Hup A adhesive solution in a pH range in which said Hup A is predominantly in a neutral form to form a Hup A adhesive solution; and adding a sheet of drug-impermeable backing laminate to coat said Hup A adhesive solution to form a pressure-sensitive adhesive formulation.
Still one further aspect of the invention is to provide for a method for providing therapeutical benefits of Hup A to a human patient diagnosed with Alzheimer disease. The method comprises preparing the aforementioned transdermal drug delivery device and administrating the same to a human patient through dermal administration for a period of time sufficient to exhibit the Alzheimer activities in the human patient.
The foregoing objects and specific construction of the present invention will become apparent and understandable from the following detailed description thereof, when read in conjunction with the accompanying figures.